Influenza infection is a recurring public health burden and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines, as carried out in animal models, and much work is devoted to strategies to induce broadly neutralizing antibodies. However, in the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, correlate with control of viral titers and reduction of disease symptoms in humans and mice. Mouse models suggest it is the lung resident memory CD8 T cells (Trm) that enable robust protection against IAV infection. Most animal models of influenza immunology rely on the sophisticated tools available for studies of inbred mice. However, our own data suggest that genetic diversity, as manifested in humans and outbred mice, can markedly affect T cell responses to influenza. Thus, incorporating genetic diversity into mouse models of influenza immunity may provide improved translational insights along with mechanistic information. However, each outbred mouse is unique, diminishing their utility. To address this, we propose to evaluate the genetically diverse Collaborative Cross (CC) mice as a potentially improved model of influenza immunity. The CC mice exhibit near outbred, but fully characterized genetic diversity, however, due to the creative breeding approach, each CC line is actually inbred and can be used for repeated studies, outcrossing to other CC lines to further enhance genetic diversity and genetic mapping studies. Our long-term goal is to determine if the CC mouse model provides improved insights into the biology of IAV- induced Trm and how these cells can be manipulated to enhance immunity to aid in development of universal influenza vaccines. We will address this long-term goal with the following specific aim: Specific Aim - Determine if genetic diversity in the CC mice will modulate IAV-specific circulating and lung resident memory CD8 T cell responses and thus, result in an improved animal model of IAV immunity that reflects the genetic diversity in outbred humans.